Hostname: page-component-586b7cd67f-r5fsc Total loading time: 0 Render date: 2024-11-22T17:37:47.310Z Has data issue: false hasContentIssue false
  • English
  • Français

Src and PI3 K inhibitors affect the virulence factors of Entamoeba histolytica

Published online by Cambridge University Press:  12 October 2012

L. LÓPEZ-CONTRERAS ,
V. I. HERNÁNDEZ-RAMÍREZ ,
Y. FLORES-GARCÍA ,
B. CHÁVEZ-MUNGUÍA  and
P. TALAMÁS-ROHANA
L. LÓPEZ-CONTRERAS
Affiliation:
Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies, Av. IPN 2508, San Pedro Zacatenco, 07360, Mexico City, Mexico
V. I. HERNÁNDEZ-RAMÍREZ
Affiliation:
Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies, Av. IPN 2508, San Pedro Zacatenco, 07360, Mexico City, Mexico
Y. FLORES-GARCÍA
Affiliation:
Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies, Av. IPN 2508, San Pedro Zacatenco, 07360, Mexico City, Mexico
B. CHÁVEZ-MUNGUÍA
Affiliation:
Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies, Av. IPN 2508, San Pedro Zacatenco, 07360, Mexico City, Mexico
P. TALAMÁS-ROHANA*
Affiliation:
Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies, Av. IPN 2508, San Pedro Zacatenco, 07360, Mexico City, Mexico
*
*Corresponding author: E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Summary

Protein kinases (PKs) of parasitic protozoa are being evaluated as drug targets. A large number of protein kinases within the protein kinome of Entamoeba histolytica strongly suggest that protein phosphorylation is a key component of pathogenesis regulation by this parasite. PI3 K and Src are kinases previously described in this parasite, but their role is poorly understood. Here, the effect of Src-1-inhibitor and PI3 K inhibitor (Wortmannin) on the virulence factors of E. histolytica was evaluated. Results show that both inhibitors affect the actin cytoskeleton and the amoebic movement. Also, the proteolytic activity is diminished by Wortmannin, but not by Src-inhibitor-1; however, the phagocytic capacity is diminished by Wortmannin and Src-1-inhibitor. Finally, we found that the virulence in vivo of E. histolytica is affected by Wortmannin but not by Src-1-inhibitor. This study opens the way for the design of anti-amoebic drugs based on kinase inhibition.

Keywords

Entamoeba histolyticaPI3 KSrcvirulence factors
Type
Research Article
Information
Parasitology , Volume 140 , Issue 2 , February 2013 , pp. 202 - 209
Copyright
Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Anamika, K., Bhattacharya, A. and Srinivasan, N. (2008). Analysis of the protein kinome of Entamoeba histolytica. Proteins 2, 995–1006.CrossRefGoogle Scholar
Barberis, L. and Hirsch, E. (2008). Targeting phosphoinositide 3-kinase gamma to fight inflammation and more. Journal of the Thrombosis Haemostasis 99, 279–285.CrossRefGoogle ScholarPubMed
Batista, E. and De Souza, W. (2004). Involvement of protein kinases on the process of erythrophagocytosis by Entamoeba histolytica. Cell Biology International 28, 243–248.CrossRefGoogle Scholar
Bhattacharya, S., Bhattacharya, A. and Petri, W. A. Jr. (2002). Examining Entamoeba. Trends in Parasitology 28, 196–197.CrossRefGoogle Scholar
Blazquez, S., Guigon, G., Weber, C., Syan, S., Sismeiro, O., Coppée, J. Y., Labruyère, E. and Guillén, N. (2008). Chemotaxis of Entamoeba histolytica towards the pro-inflammatory cytokine TNF is based on PI3 K signalling, cytoskeleton reorganization and the Galactose/N-acetylgalactosamine lectin activity. Cellular Microbiology 10, 1676–1686.CrossRefGoogle Scholar
Campos-Rodríguez, R., Jarillo-Luna, R. A., Larsen, B. A., Rivera-Aguilar, V. and Ventura-Juárez, J. (2009). Invasive amebiasis: A microcirculatory disorder? Medical Hypotheses 73, 687–697.CrossRefGoogle ScholarPubMed
Diamond, L. S., Harlow, D. R. and Cunnick, C. C. (1978). A new medium for the axenic cultivation of Entamoeba histolytica and other Entamoeba. Transactions of the Royal Society of Tropical Medicine and Hygiene 72, 431–432.CrossRefGoogle ScholarPubMed
Flores-Robles, D., Rosales, C., Rosales-Encina, J. L. and Talamás-Rohana, P. (2003). Entamoeba histolytica: a β1 integrin-like fibronectin receptor assembles a signaling complex similar to those of mammalian cells. Experimental Parasitology 103, 8–15.CrossRefGoogle ScholarPubMed
Frame, M. C., Fincham, V. J., Carragher, N. O. and Wyke, J. A. (2002). v-Src's hold over actin and cell adhesions. Nature Reviews Molecular Cell Biology 3, 233–245.CrossRefGoogle ScholarPubMed
Ghosh, S. K. and Samuelson, J. (1997). Involvement of p21racA, Phosphoinositide 3-Kinase, and Vacuolar ATPase in phagocytosis of bacteria and erythrocytes by Entamoeba histolytica: suggestive evidence for coincidental evolution of amebic invasiveness. Infection and Immunity 65, 4243–4249.CrossRefGoogle ScholarPubMed
Haque, R., Huston, C. D., Hughes, M., Houpt, E. and Petri, W. A. Jr. (2003). Amebiasis. New England Journal of Medicine 348, 1565–1573.CrossRefGoogle ScholarPubMed
Haskell, M. D., Nickles, A. L., Agati, J. M., Su, L., Dukes, B. D. and Parsons, S. J. (2001). Phosphorylation of p190 on Tyr1105 by c-Src is necessary but not sufficient for EGF-induced actin disassembly in C3H10T1/2 fibroblasts. Journal of Cell Science 114, 1699–1708.CrossRefGoogle Scholar
Hawkins, P. T. and Stephens, L. R. (2007). PI3Kγ is a key regulator of inflammatory responses and cardiovascular homeostasis. Science 5, 64–66.CrossRefGoogle Scholar
Heinz-R., R., Chen-Kao, S., A-Cary, L-Guan, J. L., Lai, J. F. and Chen, H. C. (1999). Requirement of Phosphatidylinositol 3-Kinase in focal adhesion kinase-promoted cell migration. The Journal of Biological Chemistry 274, 12361–12366.Google Scholar
Heussen, C. and Dowdle, E. B. (1980). Electrophoretic analysis of plasminogen activators in polyacrylamide gels containing sodium dodecyl sulfate and copolymerized substrates. Analytical Biochemistry 102, 196–202.CrossRefGoogle ScholarPubMed
Hunter, S., Huang, M. M., Indik, Z. K. and Schreiber, A. D. (1993). Fc gamma RIIA-mediated phagocytosis and receptor phosphorylation in cells deficient in the protein tyrosine kinase Src. Experimental Hematology 21, 1492–1497.Google ScholarPubMed
Kaplan, K. B., Swedlow, J. R., Morgan, D. O. and. Varmus, H. E. (1995). c-Src enhances the spreading of src -/- fibroblasts on fibronectin by a kinase independent mechanism. Genes and Development 9, 1505–1517.CrossRefGoogle ScholarPubMed
Labruyère, E. and Guillén, N. (2006). Host tissue invasion by Entamoeba histolytica is powered by motility and phagocytosis. Archives of Medical Research 37, 253–258.CrossRefGoogle ScholarPubMed
Li, S., Jun-Lin, G. and Chien, S. (2005). Biochemistry and biomechanics of cell motility. Annual Review of Biomedical Engineering 7, 105–150.CrossRefGoogle Scholar
Loftus, B., Anderson, I., Davies, R., Alsmark, U. C., Samuelson, J., Amedeo, P., Roncaglia, P., Berriman, M., Hirt, R. P., Mann, B. J., Nozaki, T., Suh, B., Pop, M., Duchene, M., Ackers, J., Tannich, E., Leippe, M., Hofer, M., Bruchhaus, I., Willhoeft, U., Bhattacharya, A., Chillingworth, T., Churcher, C., Hance, Z., Harris, B., Harris, D., Jagels, K., Moule, S., Mungall, K., Ormond, D., Squares, R., Whitehead, S., Quail, M. A., Rabbinowitsch, E., Norbertczak, H., Price, C., Wang, Z., Guillén, N., Gilchrist, C., Stroup, S. E., Bhattacharya, S., Lohia, A., Foster, P. G., Sicheritz-Ponten, T., Weber, C., Singh, U., Mukherjee, C., El-Sayed, N. M., Petri, W. A. Jr., Clark, C. G., Embley, T. M., Barrell, B., Fraser, C. M. and Hall, N. (2005). The genome of the protist parasite Entamoeba histolytica. Nature., London 433, 865–868.CrossRefGoogle ScholarPubMed
Meza, I. (2000). Extracellular matrix-induced signaling in Entamoeba histolytica: its role in invasiveness. Parasitology Today 16, 23–28.CrossRefGoogle ScholarPubMed
Nakahara, H., Otani, T., Sasaki, T., Miura, Y., Takai, Y. and Kogo, M. (2003). Involvement of Cdc42 and Rac small G proteins in invadopodia formation of RPMI7951 cells. Gene Cells 8, 1019–1027.CrossRefGoogle ScholarPubMed
Platek, A., Mettlen, M., Camby, I., Kiss, R., Amyere, M. and Courtoy, P. J. (2004). v-Src accelerates spontaneous motility via phosphoinositide 3-kinase, phospholipase C and phospholipase D, but abrogates chemotaxis in Rat-1. Journal of Cell Science 117, 4849–4861.CrossRefGoogle ScholarPubMed
Que, X. and Reed, S. L. (2000). Cysteine proteinases and the pathogenesis of amebiasis. Clinical Microbiology Reviews 13, 196–206.CrossRefGoogle ScholarPubMed
Ralston, K. S. and Petri, W. A. Jr. (2011). Tissue destruction and invasion by Entamoeba histolytica. Trends in Parasitology 27, 254–263.CrossRefGoogle ScholarPubMed
Ruoslahti, E., Hayman, E. G., Pierschbacher, M. and Engvall, E. (1982). Fibronectin: purification, immunochemical properties and biological activities. Methods in Enzymology 82, 803–831.CrossRefGoogle ScholarPubMed
Sanchez, A. M., Flamini, M. I., Baldacci, C., Goglia, L., Riccardo-Genazzani, A. and Simoncini, T. (2010). Estrogen receptor-α promotes breast cancer cell motility and invasion via focal adhesion kinase and N-WASP. Molecular Endocrinology 24, 2114–2125.CrossRefGoogle ScholarPubMed
Santi-Rocca, J., Rigothier, M. C. and Guillén, N. (2009). Host-microbe interactions and defense mechanisms in the development of amoebic liver abscesses. Clinical Microbiology Reviews 22, 65–75.CrossRefGoogle ScholarPubMed
Talamás-Rohana, P., and Meza, I. (1998). Interaction between pathogenic amebas and fibronectin: substrate degradation and changes in cytoskeleton organization. The Journal of Cell Biology 106, 1787–1794.CrossRefGoogle Scholar
Talamás-Rohana, P. and Ríos, A. (2000). Actin stress fibers in Entamoeba histolytica induced by fibronectin. Archives of Medical Research 31, S131–S133.CrossRefGoogle ScholarPubMed
Teranishi, F., Takahashi, N., Gao, N., Akamo, Y., Takeyama, H., Manabe, T. and Okamoto, T. (2009). Phosphoinositide 3-kinase inhibitor (wortmannin) inhibits pancreatic cancer cell motility and migration induced by hyaluronan in vitro and peritoneal metastasis in vivo. Cancer Science 100, 770–777.CrossRefGoogle ScholarPubMed
Tillack, M., Biller, L., Irmer, H., Freitas, M., Gomes, M. A., Tannich, E. and Bruchhaaus, I. (2007). The Entamoeba histolytica genome: primary structure and expression of proteolytic enzymes. BMC Genomics 8, 170–185.CrossRefGoogle ScholarPubMed
Thamilselvan, V., Craig, D. H. and Basson, M. D. (2007). FAK association with multiple signal proteins mediates pressure-induced colon cancer cell adhesion via a Src-dependent PI3 K/Akt pathway. Federation of American Societies for Experimental Biology 21, 1730–1741.CrossRefGoogle Scholar
Tsutsumi, V., Mena-Lopez, R. and Martinez-Palomo, A. (1984). Cellular bases of experimental amoebic liver abscess formation. American Journal of Pathology 130, 117–181.Google Scholar
Tsutsumi, V. and Shibayama, M. (2006). Experimental amebiasis: A selected review of some in vivo models. Archives of Medical Research 37, 210–220.CrossRefGoogle ScholarPubMed
Vanhaesebroeck, B., Ali, K., Bilancio, A., Geering, B. and Foukas, L. C. (2005). Signaling by PI3 K isoforms: insights from gene-targeted mice. Trends in Biochemical Science 30, 194–204.CrossRefGoogle Scholar
World Health Organization (2011). Initiative for vaccine research: parasitic diseases. Available at: http://www.who.int/vaccine_research/diseases/soa_parasitic/en/index1.html. Accessed April 27, 2011.Google Scholar